US4719212A - Therapeutic agent for memory disturbance - Google Patents

Therapeutic agent for memory disturbance Download PDF

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Publication number
US4719212A
US4719212A US06/948,444 US94844486A US4719212A US 4719212 A US4719212 A US 4719212A US 94844486 A US94844486 A US 94844486A US 4719212 A US4719212 A US 4719212A
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Prior art keywords
propentofylline
memory
methyl
oxohexyl
dione
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Expired - Lifetime
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US06/948,444
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English (en)
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Masayoshi Goto
Nobutaka Demura
Takashi Sakaguchi
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Hoechst AG
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Hoechst AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a therapeutic agent for memory disturbance, and more particularly, to a therapeutic agent for memory disturbance containing 1,2,3,6-tetrahydro-3-methyl-1-(5-oxohexyl)-7-propyl-purine-2,6-dione (hereinafter referred to as propentofylline) as its active ingredient.
  • a therapeutic agent for memory disturbance containing 1,2,3,6-tetrahydro-3-methyl-1-(5-oxohexyl)-7-propyl-purine-2,6-dione (hereinafter referred to as propentofylline) as its active ingredient.
  • Cerebral disturbance as used herein means both the one primarily caused by the nervous system including glia cells and the one by the cerebrovascular system.
  • Dementia as used herein means diseases manifesting psychological and physical symptoms as set forth below.
  • Dementia is classified into two large types.
  • One is Alzheimer's dementia which is a disease unknown for its cause and with cerebral nervous cells impaired.
  • the dementia of Alzheimer's type is a progressive disease in which rapidly aggravating amnesia, disorientation for time and place and depression will be observed. When the disease has been further progressed, the patient becomes highly demented and understanding of speech and ability of expression are impaired.
  • the second type is cerebrovascular dementia caused by cerebrovascular impairment.
  • the dementia patients present symptoms such as loss of intellectual capacity, disturbance of abstractive thinking, aphasia, astasia-abasia and agnosia. Disturbance of their fundamental functions lies in disturbances of the form of memory or the ability of developing retained memory.
  • Propentofylline which is used as the active ingredient in the therapeutic agent for memory disturbance according to the present invention is chemically 1,2,3,6-tetra-hydro-3-methyl-1-(5-oxohexyl)-7-propyl-purine-2,6-dione and has the structural formula shown below. ##STR1##
  • Ameliorant for cerebral circulation and metabolism is the general term covering a variety of pharmacologically active agents to which the cerebral metabolism-activating agents, the cerebral vasodilators and the platelet aggregation inhibitors belong.
  • the cereberal metabolism-activating agents are citicoline, meclofenoxate hydrochloride, solcoseryl, ifenprodil tartrate, cinepazide maleate, pyritinol hydrochloride bencyclane fumarate and calcium hopantenate.
  • cerebral vasodilators are known, in addition to ifenprodil tartrate, cinepazide maleate and bencyclane fumarate, dihydroergotoxin, nicardipine hydrochloride, pentoxifylline, cinnarizine and vinpocetine.
  • platelet aggregation inhibitors are used O-acetylsalicylic acid, sulfinpyrazone, dipyridamole and ticlopidine hydrochloride.
  • LD 50 acute toxicity
  • propentofylline may be used as an active ingredient for the treatment of humans or, particularly mammalian, animals.
  • memory formation is thought to be composed of the following three processes: At first, a memory acquiring process in which a given state of things is consolidated by learning, next comes retention of the memory, and then there is a retrieval process by which the memory is developed as needed.
  • mice In order to induce memory disturbance in mice, a solution of cycloheximide dissolved in physiological saline is administered intraperitoneally at a dose of 120 mg/kg 15 minutes prior to the training. The mice are trained by giving electric shock in the same way as above.
  • the ordinate represents memory retention (%), the abscissa days after administration of cycloheximide, the solid line the results with the control group (non-cycloheximide-treated group), the dotted line the results with the experiment group (cycloheximide-treated group) and figures in the parenthesis number of the animals subjected to the experiment. It is evident from FIG. 1 that administration of cycloheximide does not inhibit memory consolidation and retention processes but does memory retrieval process temporarily.
  • the Shuttle box was a box 26 cm in height, 44 cm in width and 24 cm in length with a floor of iron grid in which current can be delivered.
  • the box is partitioned at the center by a plate 3 cm in height. When a rat moves from one room to the other, it must jump over the barrier plate.
  • the learning was given rats at a rate of one trial per day or five trials per week.
  • Results of the experiment are graphically shown in FIG. 2, in which the ordinate represents ratio of the right response (%), the abscissa number of the trials, the dotted line results with the control group (non-propentofylline-treated group) and the solid line results with the experiment group (propentofylline-treated group).
  • Figures in the parenthesis respectively indicate the number of rats used in the experiment.
  • the mark * attached to the solid line means that there is a difference from the control group at a level of significance of 5%
  • the mark ** means that there is a difference from the control group at a level of significance of 1%.
  • Clinical doses of propentofylline in humans are in the range between 50 or 100 and 1,500 mg per day depending upon route of administration. These dosages are administered in dosage units.
  • Dosage units for oral administration in general contain 50-800, preferably 100-500 mg of propentofylline.
  • Dosage units for rectal administration in general contain from 100-1,000, preferably from 150 to 600 mg of propentofylline and dosage units of injectable preparations contain in general from 25 to 200, preferably from 50 to 150 mg of propentofylline.
  • Route of administration may be intravenous, intramuscular, oral or rectal.
  • Intravenous drip infusion may be applied for the intravenous administration in addition to the intravenous injection.
  • compositions containing propentofylline are prepared by conventional methods using conventional excipients or additives or both.
  • injectable preparations may be used, for example, a powdered preparation for injection.
  • the preparation can be produced by dissolving the drug in water in admixture with one or more appropriate water-soluble excipients such as mannitol, sucrose, lactose, maltose, glucose or fructose, dividing into vials or ampules after lyophyllizing and sealing.
  • the preparations for oral use may be conventional tablets, capsules, granules, fine granules, powders, and additionally enteric coated preparations.
  • the drug in admixture with excipients such as mannitol, sucrose, lactose, maltose, starch, silicic anhydride and calcium phosphate, lubricants such as talc and magnesium stearate, binders such as carboxymethylcellulose, methylcellulose, gelatine and arabic gum and disintegrators such as calcium carboxymethylcellulose as needed, is formed into tablets, granules, fine granules or the like, followed by coating with one or more enteric coating materials such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetylsuccinate, polyvinylalcohol phthalate, styrene-maleic anhydride copolymer, styrene-maleic acid copolymer, methyl methacrylate-methyl acrylate copolymer and methyl acrylate-methacrylic acid copolymer
  • capsules prepared by a conventional method are subjected to coating to make them enteric or enteric capsules are prepared using capsules produced from the above-mentioned enteric coating materials alone or in admixture with gelatine.
  • Rectal preparations can be formed by homogeneously blending the drug with a melt obtained by warming a lipophilic base such as cacao butter or a semisynthetic base by mixing a fatty acid triglyceride with a fatty acid monoglyceride or diglyceride in various proportions or a hydrophilic base such as polyethylene glycol or glycerogelatine and molding the blend.
  • a lipophilic base such as cacao butter or a semisynthetic base
  • a fatty acid triglyceride with a fatty acid monoglyceride or diglyceride in various proportions or a hydrophilic base such as polyethylene glycol or glycerogelatine and molding the blend.
  • FIG. 1 is a graph representing memory retention of mice treated with cycloheximide.
  • FIG. 2 is a graph representing conditioned avoidance learning of SH-rats when treated with propentofylline.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US06/948,444 1985-04-05 1986-12-29 Therapeutic agent for memory disturbance Expired - Lifetime US4719212A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP60071188A JPH062675B2 (ja) 1985-04-05 1985-04-05 記憶障害治療剤
JP60-71188 1985-04-05

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JP (1) JPH062675B2 (ja)
CA (1) CA1262685A (ja)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4965271A (en) * 1986-12-31 1990-10-23 Hoechst Roussel Pharmaceuticals, Inc. Method of inhibiting the activity of leukocyte derived cytokines
US5096906A (en) * 1986-12-31 1992-03-17 University Of Virginia Alumni Patents Foundation Method of inhibiting the activity of leukocyte derived cytokines
EP0514789A1 (de) * 1991-05-23 1992-11-25 Hoechst Aktiengesellschaft Die Verwendung von 1-(5-Oxohexyl)-3-methyl-7-n-propyl-xanthin in der Gefässchirurgie
EP0547508A1 (de) * 1991-12-11 1993-06-23 Hoechst Aktiengesellschaft Verwendung von Xanthinderivaten zur Stabilisierung der Gehirndurchblutungsautoregulation
EP0528164A3 (ja) * 1991-07-11 1994-03-02 Hoechst Ag
WO1998007400A1 (en) * 1996-08-22 1998-02-26 Theratech, Inc. Transdermal propentofylline compositions for the treatment of alzheimer's disease
US6037347A (en) * 1997-02-26 2000-03-14 Hoechst Aktiengesellschaft Combination preparation for use in dementia
US6420374B1 (en) 1990-11-30 2002-07-16 Fred Hutchinson Cancer Research Center Use of xanthines as immunosuppressants and to inhibit allograft reactions
US20040110776A1 (en) * 2002-02-22 2004-06-10 Iok-Hou Pang Use of propentofylline to control intraocular pressure

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066102A2 (en) * 1999-04-29 2000-11-09 City Of Hope Pentoxifylline, pioglitazone and metformin are inhibitors of formation of advanced glycation endproducts (age's)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4289776A (en) * 1973-06-16 1981-09-15 Hoechst Aktiengesellschaft Xanthine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4289776A (en) * 1973-06-16 1981-09-15 Hoechst Aktiengesellschaft Xanthine derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Negwer, "Organisch-Chemische Arzneimittel Und Ihre Synonyma", Akademie-Verlag, 1978.
Negwer, Organisch Chemische Arzneimittel Und Ihre Synonyma , Akademie Verlag, 1978. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5096906A (en) * 1986-12-31 1992-03-17 University Of Virginia Alumni Patents Foundation Method of inhibiting the activity of leukocyte derived cytokines
US4965271A (en) * 1986-12-31 1990-10-23 Hoechst Roussel Pharmaceuticals, Inc. Method of inhibiting the activity of leukocyte derived cytokines
US6420374B1 (en) 1990-11-30 2002-07-16 Fred Hutchinson Cancer Research Center Use of xanthines as immunosuppressants and to inhibit allograft reactions
US5475002A (en) * 1991-05-23 1995-12-12 Hoechst Aktiengesellschaft Use of 1-(5-oxohexyl)-3-methyl-7-n-propylxanthine in vascular surgery
EP0514789A1 (de) * 1991-05-23 1992-11-25 Hoechst Aktiengesellschaft Die Verwendung von 1-(5-Oxohexyl)-3-methyl-7-n-propyl-xanthin in der Gefässchirurgie
KR100237945B1 (ko) * 1991-07-11 2000-02-01 차우너 라피체 두개-뇌 외상후의 이차 뇌 손상을 치료하기 위한 크산틴 유도체 함유 약제학적 조성물
US5409935A (en) * 1991-07-11 1995-04-25 Hoechst Aktiengesellschaft Xanthine derivatives for the treatment of secondary nerve cell damage and functional disorders after cranio-cerebral traumas
EP0528164A3 (ja) * 1991-07-11 1994-03-02 Hoechst Ag
EP0547508A1 (de) * 1991-12-11 1993-06-23 Hoechst Aktiengesellschaft Verwendung von Xanthinderivaten zur Stabilisierung der Gehirndurchblutungsautoregulation
WO1998007400A1 (en) * 1996-08-22 1998-02-26 Theratech, Inc. Transdermal propentofylline compositions for the treatment of alzheimer's disease
US5762953A (en) * 1996-08-22 1998-06-09 Theratech, Inc. Transdermal propentofylline compositions for the treatment of Alzheimers disease
US6037347A (en) * 1997-02-26 2000-03-14 Hoechst Aktiengesellschaft Combination preparation for use in dementia
EP0867192A3 (de) * 1997-02-26 2000-12-06 Hoechst Aktiengesellschaft Kombinationspräparat zur Anwendung bei Demenz, enthaltend mindestens eine Verbindung die eine Acetylcholinesterase-Hemmwirkung oder muskarinerge Wirkung zeigt und eine Verbindung die den endogenen extrazellulären Adenosinspiegel erhöht
CZ298367B6 (cs) * 1997-02-26 2007-09-12 Hoechst Aktiengesellschaft Kombinovaný preparát k použití pri demenci
US20040110776A1 (en) * 2002-02-22 2004-06-10 Iok-Hou Pang Use of propentofylline to control intraocular pressure

Also Published As

Publication number Publication date
JPH062675B2 (ja) 1994-01-12
CA1262685A (en) 1989-11-07
JPS61229823A (ja) 1986-10-14

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